General Description The use of antibody-drug conjugates (ADCs) in the treatment of cancer is increasing. An ADC is composed of an antibody linked to a biologically active cytotoxic agent. The linker is typically labile, allowing for cleavage of the linker once the antibody binds to the desired target, allowing the cytotoxic agent to perform its action on the targeted cells. One ADC is currently approved for the treatment of HER2-positive metastatic breast cancer which comprises the antibody trastuzumab (Herceptin®) linked to the toxin mertansine or DM1. DM1 is structurally very complex and confers its cytotoxicity by binding to tubulin and inhibiting the assembly of microtubulesScientific Progress NCI investigators have developed novel toxins for use in ADCs or immunoconjugates. Based on a comparison with the structurally complex toxins available in the market, such as DM1, these novel toxins have increased stability in circulation which decreases the toxicity associated with them and increases selectivity since they are not getting cleaved prior to reaching the intended target. In addition, the compounds are potent inhibitors of topoisomerase making their mechanism of action distinct from those of the currently available toxins. As an example, when tested in cells, one compound (MDI 17) had an IC50 too low to be calculated and a second compound (MDI 33) had an IC50 of 50nM and an LC50 of 800nM. Investigators evaluated the toxin-antibody conjugate compared to a trastuzumab, a commercial antibody, and observed much higher growth inhibition activity for the conjugate than antibody alone. In one example, lung cancer cells (Calu-3) overexpressing Her2/neu using MTT cell toxicity assay were treated with 100 nM of either the antibody or antibody-drug conjugate, at which 54% of viable cells remained for those treated with antibody alone compared to 1.8% remaining for those treated with the antibody-drug conjugate. These compounds are structurally simple and easy to synthesize and could be used for generating a variety of drug conjugates. The toxin could be attached to an antibody or antibody fragment that recognizes a receptor on cancer cells, or to a peptide that is cleaved by tumor-specific proteases. The structure of the toxin allows it to be modified with a peptide linker that is stable, but rapidly cleaved in lysosomes after the compound is specifically taken up by cancer cellsFuture Direction

Further development involves preclinical evaluation of conjugates in multiple mouse models of cancer. Development of degradable nanomaterials targeted to tumors is also getting a momentum. Coupling the toxin to targeted nanoparticles is also a promising development for this technology

Strengths

Toxin is easy to synthesize and is stable in circulation

Toxin is cell permeable and can kill bystander cells with low receptor expression

Toxin has a different mechanism of action compared to DM1, calicheamicine and auristatin that are currently used for generation of immunoconjugates

Weaknesses

In order to use as a drug conjugate, antibodies that would be used as part of a commercial drug would need to be either developed or licensed separately from this technology

Early developmental stage. Toxins have been tested in vitro but animal data is needed

EP Application No. 20070842310 Google PatentRelevant Publications NoneInventor BioNadya Tarasova, Ph.D. Dr. Tarasova was trained as a bioorganic chemist. She obtained her Ph.D. in chemistry at Lomonosov University, Moscow, Russia in 1981. After post-doctoral training in the lab of Prof. Bent Foltmann at Copenhagen University, Denmark, she established a group working on the chemistry of proteolytic enzymes in the Chemistry Department of Lomonosov University. Dr. Tarasova joined the ABL-Basic Research Program of NCI as Visiting Scientist in 1991 and became a Staff Scientist in NCI Center for Cancer Research in 1999. She was appointed a Head of Synthetic Biologics and Drug Discovery Facility in 2008